Smoking and aging are the two greatest risk factors in lung cancer, but little is known about the mechanisms of their interaction in determining risk. The important role of epigenetic control in cancer is increasingly recognized. However, the influences of aging on the epigenome and how it mediates the relationship between genes and the environment have not been defined. The overall goal of the proposed project is to explore the role of the epigenome in modulating the effect of age on lung cancer risk in humans exposed to smoke. In this proposal, we will take advantage of four age-stratified tissue sets, consisting of laser microdissected blocks of normal lung tissue from four groups of former smokers, including young smokers with lung cancer (extreme risk group) and aged smokers without lung cancer (extreme protective group) as well as matched young smoker without cancer and old smokers with cancer. Our goal is to determine how aging and smoking interact in determining lung cancer risk, how this interaction is mediated by the epigenome and how genomic sequence polymorphisms influence changes in the epigenome, thereby affecting the aging-cancer relationship. For this purpose, we propose a systematic multidisciplinary approach to test whether age-related changes in DNA methylation and gene expression in normal lung tissue are associated with lung cancer risk and if these changes can be associated with genomic polymorphisms acting as epigenetic modifiers. To ascertain the functional relevance of observed associations, candidate gene variants will be further studied for their effect on epigenetic outcomes. We will integrate the results from whole genome bisulfite sequencing, RNA-Seq, and genotyping to reveal a major part of the epigenomic landscape in normal lung tissue exposed to tobacco smoke as a function of age and uncover the genetic variations that influence age-related alterations in the epigenome, and thereby contributing to individual lung cancer risk.